Methods of performing surgery with galactomannan polymers and borate

ABSTRACT

The present invention is directed to viscoelastic systems comprising a combination of a galactomannan polysaccharide containing composition and borate containing composition. The two compositions gel or partially gel upon combination. The present invention also discloses methods of using the systems during surgery and, in particular, eye surgery.

This application claims the benefit of Provisional Application No.60/054,307, filed Jul. 07, 1999.

BACKGROUND OF THE INVENTION

The present invention relates to viscoelastic systems and methods ofuse. In particular, the present invention relates to switchableviscoelastic systems comprising compositions containing galactomannanpolymers and borates. In general, the switchable viscoelastic systemsare administered as a Part I viscous liquid during surgery, followed bythe addition of a Part II gel-activating composition to the in situ PartI composition. The activation of the system provides a gel, allowing forthe easy and complete removal of the viscoelastic system by aspiration.

Viscoelastic systems or materials generally comprise a polymer ormixture of polymers which exhibit both a viscous (adhesive) characterand an elastic (cohesive) character. These compositions are useful forsurgery because they provide some level of coatability to the tissues tobe protected, and also are somewhat cohesive, allowing for aspiration ofthe composition following the termination of surgery. Viscoelasticcompositions are useful in a number of different surgeries and, inparticular, ocular surgeries.

Cataracts are opacities of the ocular lens which generally arise in theelderly. In order to improve eyesight, the cataractous lens is removedand an intraocular lens (“IOL”) is inserted into the capsular bag. Inorder to maximize the procedure and post-surgical recovery, viscoelasticmaterials are injected in the anterior chamber and capsular bag toprevent collapse of the anterior chamber and to protect tissue fromdamage resulting from physical manipulation.

Trabeculectomy, i.e., glaucoma filtration surgery, involves the surgicalcreation of a fistula with a conjunctival flap which allows the directdrainage of aqueous humor from the anterior chamber into theconjunctival tissue. This procedure is used as an alternative to drugtherapy, and allows for an increase in outflow of aqueous humor, therebylowering the elevated intraocular pressure associated with glaucoma. Inorder to maintain a deep chamber and enhance visualization during thesurgery, viscoelastic systems have been injected into the anteriorchamber of the eye. The viscoelastic material used for such proceduremay be difficult to aspirate out of the chamber following surgery.Ineffective or delayed removal of “lost” viscoelastic material in theanterior chamber can clog the natural drainage pores of the trabecularmeshwork and actually lead to increased intraocular pressure. Thus, aneed exists for the provision of improved viscoelastic compositionswhich are easily aspirated following filtration bleb surgery.

Vitrectomy surgery can also induce a variety of post-surgicalcomplications. Many of these complications are further potentiated indiabetic patients who are at risk for many ocular pathologies. Due tothe severity of the surgical procedure, the posterior segment surgeryprocess can cause extensive tissue damage at both the acute and chronicphases of the recovery. The chronic phase of the postsurgical period ischaracterized by more severe complications that can necessitateadditional surgery. These include an incidence of recurrent retinaldetachment, epiretinal proliferation, neovascular glaucoma, cornealproblems, vitreous hemorrhage, cystoid macular edema, and occurrence ofcataract formation within six months of surgery. While various surgicalirrigating and viscoelastic compositions are employed, the frequency ofabove-described complications still needs to be lessened by facilitatingthe recovery of vascular leakage and limiting the duration of thecellular proliferative response. Therefore, a need exists to improve thecurrent effectiveness of viscoelastic compositions used in vitrectomysurgery.

Various viscoelastic compositions are available for surgical use. Thesecompositions have employed various viscoelastic agents, such as sodiumhyaluronate, chondroitin sulfate, polyacrylamide, HPMC, proteoglycans,collagen, methylcellulose, carboxymethyl cellulose, ethylcellulose,polyvinylpyrrolidone and keratan, all of various molecular weights andconcentrations, and/or combinations thereof.

Those skilled in the art have formulated compositions containing thevarious viscoelastic agents described above to suit their particularneeds. The suitability of a given agent has depended on the variousfunction(s) which the agent is expected to perform and the surgicaltechnique being employed by the surgeon. For example, for portions ofsurgical procedures involving phacoemulsification and tissuemanipulation, e.g., cataract surgery, it has been generally preferableto use a viscoelastic agent that possesses relatively greater tissuecoatability (“adherent” or “adhesive”) properties and, consequently,relatively lesser cohesive properties. Those portions of surgicalprocedures involving manipulation of an IOL are generally better servedby viscoelastic agents that possess relatively greater cohesiveproperties and relatively lesser adherent properties to maintain space.Such agents are referred to herein as “cohesive” agents.

Various viscoelastic agents have been employed in an effort to providethe above-described needs. For example, 5% HPMC provides goodcoatability for tissue protection. However, since tissue adhesion ofthis polymer is high, HPMC is more difficult to remove from the tissue,and such efforts of removal may adversely affect the tissue. This isalso particularly critical in ocular surgery, as a residue ofviscoelastic agent remaining in the eye following surgery can block thenatural flow of aqueous humor and possibly induce glaucoma. On the otherhand, polymers with a high degree of elasticity (cohesiveness) haveprovided ease and complete removal of the viscoelastic agent. However,these highly cohesive agents do not provide the proper level ofcoatability and hence, only provide a limited level of tissueprotection. Thus, in most cases, it is desired to employ agents whichpossess extremes of both properties.

Since adhesion and cohesion properties are inversely related (i.e.,increasing one property decreases the other), current viscoelasticagents do not possess a high degree of both properties, but in general,tend to exhibit a far greater magnitude of one property and considerablyless character of the other property, or compromise between the twoproperties. In order to exploit the advantages of both types ofproperties, practitioners have employed viscoelastic regimens whichemploy two different compositions containing the different types ofagents (see, e.g., U.S. Pat. No. 5,273,056 (McLaughlin et al.)).

SUMMARY OF THE INVENTION

The present invention is directed to switchable viscoelastic systems.The viscoelastic systems of the present invention comprise a two-partgelable system, wherein the gel is created by the variable crosslinkingof a borate compound with one or more galactomannans. The gelation iscompletely reversible by manipulating pH.

In use, a Part I composition, containing one or more galactomannans inthe presence or absence of a borate compound, is administered duringsurgery as an adherent composition. When the next phase of surgery is tobe initiated, the Part II composition, comprising a crosslinking amountof a borate compound, is administered to the in situ Part I composition,thereby activating or further activating the gelation of thegalactomannan containing composition. The admixture of Part I and IIforms a highly cohesive composition which provides space maintenancecapabilities and easy aspiration of the viscoelastic system at the closeof surgery.

The viscoelastic systems of the present invention provide the advantagesof a switchable gelling system, wherein a composition may beadministered as a liquid or partially gelled liquid and later convertedto a gel. Accordingly, one advantage of the viscoelastic systems of thepresent invention is that they provide optimal levels of both adhesiveproperties and cohesive properties in a single system. Another advantageof the systems is that they are switchable, i.e., they may be convertedfrom an adherent system to a cohesive system during surgery. Currentviscoelastic compositions have employed hyaluronic acid and othernaturally occuring polymers. The preparation and sterilization of theseagents is generally expensive, resulting in relatively expensiveviscoelastic compositions. The systems of the present invention compriserelatively inexpensive agents. Thus, another advantage of the systems ofthe present invention is that they are relatively low in cost toproduce. Still another advantage of the systems of the present inventionis that they provide a relatively high degree of reproducibility of thegel charcteristics through various types and sources of galactomannan(see, FIG. 3). This feature allows for the interchange of sourcingwithout extensive reworking of the compositions of the presentinvention.

The methods of the present invention involve the surgical use of thecompositions of the present invention.

The present invention is also directed to methods of sterilization ofthe galactomannans involving autoclaving.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the gelling characteristics of variousconcentrations of guar gum in the presence of borate, relative to pH.

FIG. 2 is a graph illustrating the gelling characteristics of variousconcentrations of borate in the presence of guar gum, relative to pH.

FIG. 3 is a graph illustrating the uniformity of the gellingcharacteristics of three different types/sources of guar gum.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to viscoelastic systems which comprisecompositions containing one or more galactomannan polysaccharide(s) andone or more borate compound(s). The present invention is also directedto methods of using these compositions to treat various surgeries and,in particular, ophthalmic surgeries such as cataract, trabeculectomy andvitrectomy surgeries.

The compositions of the present invention comprise a two-part system.The two compositions are formulated in such a way that an increase ordecrease of the gelation of the first part is manipulated by theadmixture of the second part with the first part. Accordingly, the firstpart, referred to herein as “Part I,” will comprise one or moregalactomannan polymer(s) and optionally an amount of a borate compound.In general, the second part, referred to herein as “Part II,” willcomprise a crosslinking amount of at least one borate compound. As usedherein, the term “crosslinking amount” refers to that amount of a boratecompound sufficient to facilitate the borate-galactomannan crosslinkingof the Part I and Part II compositions, such that the admixture of thecompositions increases in viscosity and cohesiveness over the Part Icomposition. Alternatively, the Part I composition may contain both thegalactomannan and borate compounds at a slightly acidic pH relative tophysiological pH, and the Part II composition may contain a salinesolution capable of increasing the pH of the Part I composition, suchthat gelation is accomplished by the admixture of Parts I and II.

Is The types of galactomannan that may be used in the present inventionare typically derived from guar gum, locust bean gum and tara gum. Asused herein, the term “galactomannan” refers to polysaccharides derivedfrom the above natural gums or similar natural or synthetic gumscontaining mannose or galactose moieties, or both groups, as the mainstructural components. Preferred galactomannans of the present inventionare made up of linear chains of (1-4)-β-D-mannopyranosyl units withα-D-galactopyranosyl units attached by (1-6) linkages. With thepreferred galactomannans, the ratio of D-galactose to D-mannose willvary, but generally will be from about 1:2 to 1:4. Galactomannans havinga D-galactose:D-mannose ratio of about 1:2 are most preferred.

In order to limit the extent of cross-linking and provide a softer gelcharacteristic, chemically modified galactomannans may be utilized.Accordingly, chemically modified variations of the polysaccharidesdescribed above are also included in the “galactomannan” definition. Forexample, hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropylsubstitutions may be made to the galactomannans of the presentinvention. If it is desired to modify the galactomannans, non-ionicsubstitutions of the galactomannans, such as those containing alkoxy andalkyl (C1-C6) groups are particularly preferred (e.g., hydroxylpropylsubstitutions). Substitutions in the non-cis hydroxyl positions are mostpreferred. An example of non-ionic substitution of a galactomannan ofthe present invention is hydroxypropyl guar. with a molar substitutionratio of less than about 0.6.

The borate compounds which may be used in the compositions of thepresent invention are boric acid and other pharmaceutically acceptablesalts such as sodium borate (borax) and potassium borate. As usedherein, the term “borate” refers to all pharmaceutically suitable formsof borates.

The Part I compositions of the viscoelastic systems of the presentinvention comprise one or more galactomannan(s) in an amount of fromabout 0.5 to 5.0% weight/volume (“w/v”). Preferably, the compositionswill contain 1.0 to 3.0% (w/v) of galactomannan, and most preferably,the compositions will contain 1.0 to 2.0% (w/v) of galactomannan. Asstated above, the Part I composition may optionally contain a boratecompound. If a viscosity greater than that of a non-crosslinkedgalactomannan Part I composition is desired. than a variablecrosslinking amount of a borate compound may be added to the compositionto facilitate a minor to partially gelled nature (and greater viscosity)of the Part I composition. Such an amount of a borate compound willdepend on the amount of galactomannan present, the tonicity and pHlevels of the Part I composition, as well as the presence of otheringredients. In general, such an amount of borate will be up to 5.0%(w/v).

The Part II compositions of the viscoelastic systems of the presentinvention will generally comprise a crosslinking amount of a boratecompound. In general, such an amount will be from about 0.05 to 5%(w/v). Preferably, the compositions will contain 0.05 to 2.0% (w/v) of aborate compound, and most preferably, the compositions will contain 0.1to 0.75% (w/v) of a borate compound. Alternatively, the Part Icomposition will comprise all of the borate compound, wherein the PartII composition will comprise an amount of tonicity and pH affectingagent(s) necessary to facillitate gelation of the admixture of Part Iand Part II.

The particular amounts of the galactomannan and borate will vary,depending on the particular gelling properties desired. In general, theborate or galactomannan concentration may be manipulated in order toarrive at the appropriate viscosity of the Part I composition, and theappropriate viscosity/cohesiveness of the combination of the Part I andPart II compositions. As shown in FIGS. 1 and 2, manipulating either theborate or galactomannan concentration provides stronger or weakergelation at a given pH. If a strongly gelling composition is desired,then the borate or galactomannan concentration may be increased. If aweaker gelling composition is desired, such as a partially gellingcomposition, then the borate or galactomannan concentration may bereduced. Other factors may influence the gelling features of thecompositions of the present invention, such as the nature andconcentration of additional ingredients in the compositions, such assalts, pharmaceutically active agents, and so on. Generally, preferrednon-gelled Part I compositions of the present invention, i.e.,compositions exhibiting a relatively high adhesive character, will havea viscosity of from about 500 to 50,000 cps.

The galactomannans of the present invention may be obtained fromnumerous sources. Such sources include guar gum, locust bean gum andtara gum, as further described below. Additionally, the galactomannansmay also be obtained by classical synthetic routes or may be obtained bychemical modification of naturally occurring galactomannans.

Guar gum is the ground endosperm of Cyamopisis tetragonolobus (L.) Taub.The water soluble fraction (85%) is called “guaran”(molecular weight of220,000), which consists of linear chains of (1-4)-β-D mannopyranosylunits with α-D-galactopyranosyl units attached by (1-6) linkages. Theratio of D-galactose to D-mannose in guaran is about 1:2. The gum hasbeen cultivated in Asia for centuries and is primarily used in food andpersonal care products for its thickening property. It has five to eighttimes the thickening power of starch. Its derivatives, such as thosecontaining hydroxypropyl or hydroxypropyltrimonium chloridesubstitutions, have been commercially available for over a decade. Guargum can be obtained, for example, from Rhone-Polulenc (Cranbury, N.J.).Hercules. Inc. (Wilmington, Del.) and TIC Gum, Inc. (Belcamp, Md.).

Locust bean gum or carob bean gum is the refined endosperm of the seedof the carob tree, ceratonia siliqua. The ratio of galactose to mannosefor this type of gum is about 1:4. Cultivation of the carob tree is oldand well known in the art. This type of gum is commercially availableand may be obtained from TIC Gum, Inc. (Bekamp, Md.) and Rhone-Polulenc(Cranbury, N.J.).

Tara gum is derived from the refined seed gum of the tara tree. Theratio of galactose to mannose is about 1:3. Tara gum is not produced inthe U.S. commercially, but the gum may be obtained from various foreignsources.

Substituted galactomannans are commercially available from Rhone-Poulenc(Cranbury, N.J.).

Other ingredients may be added to the Part I compositions of the presentinvention. Such ingredients generally may include tonicity adjustingagents, active pharmaceutical agent(s) and pH adjusting agents. Ifrelatively insoluble pharmaceutical agent(s) are to be added to the PartI compositions, then various solubilizers may be employed to aid in thesolubilization of the agent(s). Other polymer or monomeric agents suchas polyethylene glycol and glycerol may also be added for specialprocessing. Tonicity agents useful in the compositions of the presentinvention may include salts such as sodium chloride, potassium chlorideand calcium chloride; non-ionic tonicity agents may include propyleneglycol and glycerol; solubilizing agents may include Cremophor EL® andtween 80; and pH adjusting agents may include hydrochloric acid, Tris,triethanolamine and sodium hydroxide. In general, the Part Icompositions will be packaged for unit dose application. With thesetypes of packagings, the product is sterile packaged and used for onesurgical procedure, with any remaining product discarded. If, however,the Part I compositions of the present invention are packaged formulti-dose application, a suitable preservative will be added to thecomposition. Suitable preservatives may include, for example,benzalkonium chloride, polyquaternium-1 and polyhexamethylene biguanide.The above listing of examples is given for illustrative purposes and isnot intended to be exhaustive. Examples of other agents useful for theforegoing purposes are well known in the field of ophthalmic formulationand are contemplated by the present invention.

Other agents may be added to the Part II compositions of the presentinvention. Such ingredients include those generally described in thepreceding paragraph. The primary function of Part I compositions,however, is to activate a gel in combination with the Part Icomposition. Thus, while the Part I composition is added to the tissuesitus for therapeutic purposes, the Part II composition is generallyonly utilized to prepare a cohesive and hence, easily aspiratable andquickly removable gel combination of Part I and Part II. Therefore, thePart II compositions generally will only comprise other ingredientsnecessary to transfer the crosslinking amount of a borate compound tothe Part I composition. Such ingredients typically will be salts orother tonicity agents, and water. As stated above, if the Part Icomposition optionally contains both the galactomannan and boratecompound at a slightly acidic pH, then the Part II composition may beformulated to deliver an amount of tonicity agent/pH modifying agent tofacilitate gel formation. In general, similar to the Part Icompositions, the Part II compositions will typically be formulated forunit dose application. If, however, the Part II compositions of thepresent invention are packaged for multi-dose application, a suitablepreservative will be added to the composition. Suitable preservativesmay include those described above.

Sterilization of the galactomannan polysaccharide can be accomplished byautoclaving. Since the polymers undergo depolymerization at the extremeconditions of autoclaving, non-aqueous autoclaving is generallypreferred. This can be accomplished by dispersing the polymer in asuitable organic liquid such as low molecular weight polyethyleneglycols. The resulting suspension may then be autoclaved to sterilizethe polymer. The sterilized polymer is then hydrated aseptically, priorto admixture with the other ingredients. The following exampleillustrates a novel method of sterilizing a galactomannan polysaccharideof the present invention:

EXAMPLE 1

Preliminarily, a compounding vessel (20 L stainless steel pressure can),a 0.2 micron sterilizing filter, a receiving vessel (20 L carboy), a 4.5micron polishing filter, a 0.2 micron sterilizing filter, a vent filter,and the filling equipment are sterilized by autoclaving.

In a beaker equipped with an overhead agitator, add the weighed amountof polyethylene glycol 400 (200 g). While mixing slowly disperse theweighed amount of hydroxypropyl (“HP”)Guar gum (100 g). Mix untilcompletely homogeneous. In a 500 ml Schott bottle, equipped with amagnetic stir bar, weigh exactly 120.0 g of the HPGuar gum/PEG-400dispersion. Prepare to sterilize by autoclaving. In a second identical500 ml Schott bottle weigh exactly 120.0 g of the same dispersion.Prepare to use as a dummy during the autoclaving cycle. To both bottlesadd 1.3 ml of purified water (amount equivalent, by volume, of themicroorganism suspension used to inoculate the bottles during thevalidation study). Mix both bottles for 10 minutes using a magnetic stirplate. Autoclave the HPGuar gum/PEG-400 dispersion using the validatedtime-temperature cycle of 80 minutes at 125° C.

The other set of ingredients to be included in the final formulation maybe prepared separately by various methods known in the art. Theresultant mixture can be added by sterile filtration to the compoundingvessel, along with the HPGuar gum/PEG-400 preparation.

Aseptically transfer the sterilized HPGuar gum/PEG-400 dispersion intothe pre-sterilized compounding vessel. Rinse the bottle content withsterilized purified water. Bring the content of the compounding vesselto exactly 95% of the theoretical batch weight (19.0 liters or 19.06 Kg)using sterile room temperature purified water. Allow the HPGuar gum/PEGslurry to hydrate while mixing, at moderate speed, in the compoundingvessel for a minimum of 2 hours. Transfer the contents of thecompounding vessel through a 4.5 micron pre-sterilized polishing filterinto the pre-sterilized receiving vessel equipped with a stir bar. Therewill be some loss of the contents due to the product held in filterhousing and filter cartridge. (If a pressure can is used as compoundingvessel, the recommended pressure for clarification filtration isapproximately 30 psi.) Check and adjust pH, if necessary, to 6.9-7.1(target 7.0) using 1N NaOH or 1N HCl. Approximately 3-4 ml of 1N NaOHper 1 liter of final batch weight is needed to achieve the desired pH.QS to final batch weight using sterile purified water. Mix at low speedfor a minimum of 30 minutes.

The methods of the present invention involve the use of variousviscoelastic agents having different adherent or cohesive properties.Those skilled in the art will recognize that the systems of the presentinvention may be employed by the skilled surgeon in a variety ofsurgical procedures.

For portions of surgical procedures involving phacoemulsification and/ortissue manipulation, e.g., cataract surgery, Part I viscoelasticcompositions that possess relatively greater adherent properties andrelatively lesser cohesive properties will provide superior tissueprotection. For Part I compositions such as these, which are beingemployed primarily for protective purposes, a functionally desirableviscosity will be a viscosity sufficient to permit a protective layer ofsuch agent to remain on the tissue or cells of concern during thesurgical step(s) being performed. Such viscosity will typically be fromabout 500 cps to about 50,000 cps (at shear rate of 2 sec⁻¹ and 25° C.),and preferably will be about 10,000 to about 40,000 cps. Such adherentagents are capable of providing the protective function previouslydiscussed, yet are not prone to inadvertent removal, which couldjeopardize the delicate tissue being protected. The Part I adherentcompositions of the present invention may also be used for spacemaintainance purposes prior to application of Part II compositions.

Following the phacoemulsification step, those portions of surgicalprocedures involving intraocular lens manipulation are generally betterserved by gel-activated viscoelastic systems (Part I and Part IIcompositions) that provide space filling requirements and ease ofremoval. Such agents are referred to herein as “cohesive” agents. Forhighly cohesive gel-activated systems (i.e., combined Part I and Part IIcompositions) which are being employed primarily for space maintainancepurposes as opposed to protective purposes, a functionally desirableviscosity will be a viscosity sufficient to permit the skilled surgeonto use such agent as a soft tool to manipulate or support the tissue ofconcern during the surgical step(s) being performed. Such highlycohesive agents are capable of maintaining intraocular space andmanipulating tissue without adhering to it. When their purpose has beenserved, they can, because of their cohesive properties, be readilyremoved with minimal trauma to the surrounding tissue. Furthermore, whena Part I composition of the present invention is gel activated by theaddition of a Part II composition of the present invention, the gel(having greater cohesive property) may be easily and completely removed.thereby minimizing complications resulting from excessive aspirating ofthe less cohesive agents and the possible intraocular pressure spikeresulting from the incomplete removal of the adherent compositions insitu.

The present invention may also be used in corneal transplant surgery. Inconjunction with the removal of the patient's corneal button, it isdesirable to replace the aqueous humor with a highly viscous agent thatwill provide a firm bed to support the donor cornea, yet be susceptibleto easy removal upon completion of the surgery. The donor graft, on theother hand, requires maximum protection from the surgical trauma andshould therefore be coated with a different, more adherent agent.Corneal transplant surgery also involves the risks of inflammation andcellular damage. Thus, the compositions of present invention are alsouseful in this type surgery.

The compositions of the present invention may also be used in posteriorsegment surgery. In a retinal detachment procedure, for example, ahighly viscous, cohesive composition of the present invention will beused to manipulate the retina into position against the basementmembrane of the choroid. Small amounts of a more adherent composition ofthe present invention may be injected behind the retina before or aftersuch manipulation to temporarily maintain the contact between the retinaand basement membrane while more permanent attachment procedures wellknown to those skilled in the art are performed (e.g. tacking or laserwelding).

The methods of the present invention are also directed to using thesystems of the present invention to ameliorate complications arisingfrom glaucoma filtration surgery. Glaucoma filtration surgery involvesthe surgical creation of a fistula with a conjunctival flap which allowsthe direct drainage of aqueous humor from the anterior chamber into theconjunctival tissue thereby lowering the elevated intraocular pressureassociated with glaucoma. However, in many patients, the filtration“bleb” becomes scarred or healed over so that aqueous drainage can nolonger occur. In order to maintain a deep chamber and enhancevisualization during the surgery, the viscoelastic systems of thepresent invention will be injected into the anterior chamber of the eye.The addition of these systems will ameliorate inflammatory conditionsresulting from the surgery, fibroplasia and decrease bleb failure.

The following examples further illustrate preferred ophthalmicviscoelastic compositions of the present invention:

EXAMPLE 2

The following is an example of a viscoelastic system comprising a Part Iviscoelastic composition and Part II gel-activation composition:

Part I: Compound Amount % (w/v) Guar Gum 2.0 Polyethylene Glycol 400(“PEG-400”) 2.0 Sodium Chloride 0.6 Sodium Hydroxide/Hydrochloric AcidpH 7.4 Purified Water QS

The above formulation is prepared by first dispersing guar gum inPEG-400, and autoclaving the suspension (Part I). Sodium chloride isthen dissolved in 50% of the volume of water and sterile filtered in areceiving vessel as Part II. Part I is then added to Part II asepticallyand the polymer is allowed to hydrate. The pH may then be adjustedaseptically and the batch is then brought to final weight (volume). Thecombined solution is then passed through a 1.0 μm polish filter,aseptically, to remove the particulates.

Part II: Compound Amount % (w/v) Sodium Borate 0.25 Sodium Chloride 0.4Sodium Hydroxide/Hydrochloric Acid pH 7.4 Purified Water QS

The invention in its broader aspects is not limited to the specificdetails shown and described above. Departures may be made from suchdetails within the scope of the accompanying claims without departingfrom the principals of the invention and without sacrificing itsadvantages.

What is claimed is:
 1. A method of performing surgery on an eye, whichcomprises: instilling into the eye a Part I viscous compositioncomprising one or more galactomannan; and adding to the Part Icomposition in the eye a Part II crosslinking composition comprising acrosslinking amount of one or more borate compound to form a cohesive,gelled combination of the Part I and Part II compositions having agreater viscosity and cohesivity than the viscosity and cohesivity ofthe Part I composition alone.
 2. The method of claim 1, wherein theconcentration of the galactomannan in the Part I composition is about0.5 to 5.0% (w/v) and the concentration of the borate compound in thePart II composition is about 0.05 to 2.0% (w/v).
 3. The method of claim1, wherein the galactomannan is selected from the group consisting ofguar gum, locust bean gum, tara gum and chemically modified derivativesthereof.
 4. The method of claim 1, wherein the borate compound isselected from the group consisting of boric acid, sodium borate,potassium borate and combinations thereof.
 5. The method of claim 1,wherein the galactomannan is hydroxypropyl guar and the borate compoundis boric acid.
 6. The method of claim 5, wherein the hydroxypropyl guaris in a concentration of 1.0 to 3.0% (w/v) and boric acid is in aconcentration of 0.1 to 0.75% (w/v).
 7. The method of claim 1, whereinthe galactomannan is guar gum and the borate compound is boric acid. 8.The method of claim 7, wherein the Part I composition comprises guar gumin a concentration of 1.0 to 3.0% (w/v) and the Part II compositioncomprises boric acid in a concentration of 0.1 to 0.75% (w/v).
 9. Themethod of claim 1, wherein the Part I composition further comprises oneor more pharmaceutically active agent(s).
 10. The method of claim 9,wherein the pharmaceutically active agent is selected from the groupconsisting of: anti-hypertensive, anti-glaucoma, neuro-protective,